Periodic Reporting for period 4 - Brain Health Toolbox (The Brain Health Toolbox: Facilitating personalized decision-making for effective dementia prevention)
Reporting period: 2023-08-01 to 2024-07-31
Dementia and Alzheimer’s disease (AD) are a major public health challenge in the context of worldwide population aging. Brain pathology progresses gradually over a long time period before dementia onset, thus creating a window of opportunity for prevention. Early identification of at-risk individuals who are also most likely to respond to interventions is crucial. Due to the complex, multifactorial nature of dementia/AD, multimodal interventions targeting several risk factors and disease mechanisms simultaneously may also be needed for effective prevention.
The Brain Health Toolbox has focused on connecting dementia risk prediction with multimodal lifestyle interventions for risk reduction. This has involved developing risk/disease models and prediction algorithms and testing them in actual prevention trials. The multimodal interventions covered healthy lifestyle changes in several domains at the same time, e.g. combination of physical exercise, dietary advice, cognitive training, social activities and monitoring and management of vascular and metabolic risk factors (FINGER intervention model). During the project a new multimodal prevention trial was designed, combining healthy lifestyle changes with pharmacological treatment. This new FINGER 2.0 combination therapy model for dementia risk reduction is highly relevant because it can also be adapted in the future as new medications for dementia diseases emerge.
The Brain Health Toolbox has focused on connecting dementia risk prediction with multimodal lifestyle interventions for risk reduction. This has involved developing risk/disease models and prediction algorithms and testing them in actual prevention trials. The multimodal interventions covered healthy lifestyle changes in several domains at the same time, e.g. combination of physical exercise, dietary advice, cognitive training, social activities and monitoring and management of vascular and metabolic risk factors (FINGER intervention model). During the project a new multimodal prevention trial was designed, combining healthy lifestyle changes with pharmacological treatment. This new FINGER 2.0 combination therapy model for dementia risk reduction is highly relevant because it can also be adapted in the future as new medications for dementia diseases emerge.
Connecting disease risk estimation with prediction of response to multimodal lifestyle interventions was done by using several complementary approaches, e.g. observational and interventional randomized controlled trial data, analysis ranging from machine learning to traditional statistics, and multi-dimensional predictors and outcomes (e.g. cognitive, clinical, blood, cerebrospinal fluid, brain imaging markers, genetic and modifiable factors).
Among the main results, multimodal lifestyle interventions for dementia risk reduction were particularly beneficial when targeted specifically to at-risk individuals. Overall, earlier interventions were more likely to show benefit, although there was still room for risk reduction in people with cognitive impairment who did not yet have dementia (prodromal AD). People with higher genetic risk for AD also benefited from early interventions. Metabolomic and other biomarker analyses provided new knowledge on potential intervention mechanisms. These findings provide an important alternative for dementia risk reduction because, as shown in the project, many at-risk people may not be eligible for new AD drugs.
Project results were also used for the development of World-Wide FINGERS (WW-FINGERS), the first global network of multimodal dementia prevention trials (currently 68 member countries). This has facilitated harmonisation across trial protocols and joint analyses that can continue to provide highly valuable knowledge as more trials will be conducted by network members, including in low/middle income countries.
Some at-risk individuals may need more than lifestyle intervention for optimal benefit. To design the first multimodal prevention trial combining lifestyle-based and pharmacological intervention, a drug repurposing approach was used due to several AD drug trial failures during 2019-2020. Metformin, commonly used for diabetes treatment, was identified as a suitable putative disease-modifying drug. A novel updated FINGER 2.0 precision prevention model was developed, combining multidomain lifestyle intervention with metformin. Although routinely used for diabetes, this combination therapy has not been previously tested for dementia risk reduction. MET-FINGER is the first WW-FINGERS trial testing a FINGER 2.0 combination therapy model and may provide a much-needed therapeutic approach for a large group of people at-risk for dementia who are asymptomatic and/or not eligible for new AD drugs.
Among the main results, multimodal lifestyle interventions for dementia risk reduction were particularly beneficial when targeted specifically to at-risk individuals. Overall, earlier interventions were more likely to show benefit, although there was still room for risk reduction in people with cognitive impairment who did not yet have dementia (prodromal AD). People with higher genetic risk for AD also benefited from early interventions. Metabolomic and other biomarker analyses provided new knowledge on potential intervention mechanisms. These findings provide an important alternative for dementia risk reduction because, as shown in the project, many at-risk people may not be eligible for new AD drugs.
Project results were also used for the development of World-Wide FINGERS (WW-FINGERS), the first global network of multimodal dementia prevention trials (currently 68 member countries). This has facilitated harmonisation across trial protocols and joint analyses that can continue to provide highly valuable knowledge as more trials will be conducted by network members, including in low/middle income countries.
Some at-risk individuals may need more than lifestyle intervention for optimal benefit. To design the first multimodal prevention trial combining lifestyle-based and pharmacological intervention, a drug repurposing approach was used due to several AD drug trial failures during 2019-2020. Metformin, commonly used for diabetes treatment, was identified as a suitable putative disease-modifying drug. A novel updated FINGER 2.0 precision prevention model was developed, combining multidomain lifestyle intervention with metformin. Although routinely used for diabetes, this combination therapy has not been previously tested for dementia risk reduction. MET-FINGER is the first WW-FINGERS trial testing a FINGER 2.0 combination therapy model and may provide a much-needed therapeutic approach for a large group of people at-risk for dementia who are asymptomatic and/or not eligible for new AD drugs.
Progress beyond the state of the art has included:
- Predicting early brain pathology and cognitive trajectories in real-life interventions and clinical setting
- New evidence from intervention studies on genetic-lifestyle interactions, the window of opportunity for dementia risk reduction, and potential intervention mechanisms
- Development of the first global network for multimodal dementia prevention trials
- The first multimodal precision prevention trial design combining lifestyle intervention with a repurposed putative disease-modifying drug.
Overall, the project has significantly contributed to innovative combination therapy approaches targeted to at-risk individuals for early dementia risk reduction.
- Predicting early brain pathology and cognitive trajectories in real-life interventions and clinical setting
- New evidence from intervention studies on genetic-lifestyle interactions, the window of opportunity for dementia risk reduction, and potential intervention mechanisms
- Development of the first global network for multimodal dementia prevention trials
- The first multimodal precision prevention trial design combining lifestyle intervention with a repurposed putative disease-modifying drug.
Overall, the project has significantly contributed to innovative combination therapy approaches targeted to at-risk individuals for early dementia risk reduction.